The kidneys function to maintain a constant composition of the extracellular fluid in the body, but regulation cannot be perfect and, in states producing hyper- or hyponatremia the plasma osmolarity may deviate from a normal 285 mosm/liter to as high as 360 and as low as 220 mosm/liter. Such variations do not appear to impair tissue function (provided the change is gradual). Moreover, individual cells appear to adapt to non-isotonic conditions by maintaining a cell volume close to that in isotonic plasma. The aim of the proposed research is to study the mechanism of this adaptation. For the red cell to survive in the circulation it must defend its volume within narrow limits and the human red cell will be the focus of these studies. Cation shifts seem to underly the adaptation of mammalian cells to non-isotonic conditions and it is proposed to study cation fluxes in red cells exposed to various tonicities. Na and K ions may be translocated by an active pump and also by a passive co-transport system which can move both ions together in the same direction. Increases in membrane calcium can also produce large potassium leaks out of the cell. All these modes of cation transport will be studied to provide insight into how mammalian cells defend their normal volume. Some widely used drugs can affect cation fuxes and their influence on volume regulation will be studied. Cardiac glycosides such as digoxin or ouabain specifically inhibit the active cation pump, while the diuretic furosemide inhibits the co-transport system for NA plus K ions. Chlorpromazine affects calcium transport into mitochondria and its effects on both cation transport and volume will be studied in red cells. Some of the important pharmacological effects of these agents may result from their effect on volume regulation.